Domodossola was the chief town of the Lepontii when the Romans conquered the region in 12 BCE.

During World War II Domodossola was part of an uprising against the Germans, whereby the valley of Ossola declared itself a free partisan republic in September 1944 and broke away from Fascist Italy. The rebellion was crushed by German troops within less than two months, but was an important symbol for anti-fascist movements within Italy until the end of the war.